The objective is to investigate the possible significance of the low level in rheumatoid arthritis of a recently discovered ultrafiltrable serum endogenous inhibitor of the aggregation of human immunoglobulin G (IgG). The hypothesis is that this inhibitor is a histidine-cystine-copper complex and that the low serum histidine of rheumatoid arthritis produces a decreased level of this complex in serum and synovial fluid. Histidine-cystine-copper inhibits the aggregation of human IgG in vitro, apparently by blocking specifically those sulfhydryl groups involved in sulfhydryl-disulfide interchange. The antirheumatic drugs, gold, penicillamine, and possibly chloroquine inhibit denaturation in vitro by the same mechanism. It is proposed that a deficiency of the endogenous inhibitor may contribute to the pathogenesis of rheumatoid arthritis by permitting SH-dependent, hyaluronate-augmented, mechanical or chemical aggregation of synovial fluid IgG. The proposed inflammatory and antigenic pseudoimmune complex thus generated could theoretically set off a sequence of immunological and enzymatic events leading to rheumatoid arthritis and rheumatoid factor. The endogenous inhibitor will be assayed by measuring the inhibitory effect of serum ultrafiltrate on the heat aggregation of human IgG. The specific aims are to (a) determine the specificity for rheumatoid arthritis of a low serum level of the inhibitor, (b) characterize the normal endogenous inhibitor, (c) improve, especialy by the use of IgG with a known copper content, the assay for the inhibitor, (d) study the mechanism of action of the inhibitor, (e) study of the effect of ultrafiltrate on the mechanical aggregation of IgG, (f) measure the serum cystine in RA, (g) identify the types of protein aggregated when synovial fluid is mechanically denatured, (d) determine the effect of ultrafiltrate and SH-blockers on the formation of inflammatory material by the aggregation of human IgG and synovial fluid by head and mechanical action, and (i) correlate the serum and synovial fluid histidine concentrations in patients with rheumatoid arthritis and other conditions.